Safety indications in mouse models treated with full doses of MEK inhibitors and SHP099

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Published: 25 Apr 2018
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Dr Carmine Fedele - Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical, New York, USA

Dr Fedele speaks with ecancer at AACR 2018 about adding an SHP2 inhibitor to MEK targeted therapy to overcome drug resistance.

He describes results from in vitro and in vivo cancer models, with significant and cancer specific toxicity in mice model treated with full doses of MEK inhibitors and SHP099

The title of my talk is SHP2 inhibition overcomes the adaptive resistance induced by MEK inhibitors in several cancer models. SHP2 is the first oncogenic tyrosine phosphatase reported and basically plays an important role in cell proliferation because it regulates the MAP kinase pathway that is one of the major pathways involved in cell survival and proliferation. Another point that I’m touching on in this talk is the adaptive resistance. One of the major problems with targeted therapy, targeted therapy is not like chemotherapy that is a broad treatment that is not specific for cancer cells, it touches both cancer cells and normal cells while targeted therapy is specific to target cancer cells. But cancer cells are smart, they adapt to the treatment that you give to them. One of the mechanisms of this adaptive resistance is the upregulation of the tyrosine kinase receptor that refuels the survival pathway and then the cells become stronger and able to survive the treatment.

But SHP2 is a protein that works downstream of many tyrosine kinase receptors. We thought that targeting these molecules can be a viable strategy to overcome the resistance. To test this hypothesis we performed an in vitro assay in which we tested around forty different cell lines for different kinds of cancer like pancreatic, triple negative breast cancer, ovarian cancer. We tested the viability using the different drugs and we found that the combination of these two drugs strictly reduced the cell number in all these cancer models. Then we dissected the molecular mechanism as the basis of this phenotype and finally we have also seen that this combination is effective in the in vivo model of cancer as a xenograft and also a GEM model.

What might you expect to see coming from this research?

For example, for what concerns MEK inhibitors in treating pancreatic cancer there is a clinical trial. But the major problem is the onset of adaptive resistance. So maybe combining the treatment of patients with MEK inhibitors and adding this new molecule that has been recently discovered by Novartis that is a specific SHP2 inhibitor may be more effective in curing this kind of disease as pancreatic cancer that is almost undruggable and a very, very aggressive disease.